Postpanóptico y Sinóptico, Sociedades del ControlSociedades del Control

Over the past two decades, utility of supercritical fluids (SCF) has gained substantial momentum in the pharmaceutical industry. Although customarily used in the food industry for extraction (caffeine, essential oils, etc.) or in separation science for purification, the SCF offer promising opportunities in the development of special-ized drug delivery systems such as particle design, nanoparticles, and amorphous dispersions. The key advantage of using supercritical fluids lies in their liquid- and gas-like properties that provide excellent media for solubilization with very low sol-vent burden. Due to the flexibility in designing the system, SCF can be used either as a solvent or antisolvent depending on the solubility of API and the stabilizing polymer. Its applications to ASD development is as diverse as the technology itself, e.g.:

• HME: As a processing aid in HME, SCF can serve multiple purposes ranging from lowering the melt viscosity, lowering processing temperature, modifying solubility of the drug in the molten polymer, and increasing the porosity of the extrudates that can improve dissolution and compaction.

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• Spray drying: As an extraction solvent, SCF can be used to extract residual solvents from spray-dried material.

• Microprecipitation: As a stand-alone system, depending on the solubility, SCF may be used as a solvent or an antisolvent for microprecipitation technology that is akin to rapid expansion of supercritical solvent (RESS) or SCF as an antisolvent for precipitation (SAS).

Depending on how SCF is used, several techniques have evolved over the years especially in the particle engineering area. The commonly used variations of different processes are delineated below:

• Rapid expansion of supercritical solutions (RESS)

• Gas antisolvent precipitation (GAS)

• Supercritical antisolvent precipitation (SAS)

• Precipitation with compressed fluid antisolvent (PCA)

• Solution-enhanced dispersion by supercritical fluids (SEDS)

• Precipitation from gas-saturated solutions (PGSS)

Although there are very few case studies where SCF has been evaluated for produc-tion of ASD, the literature is rich with its applicaproduc-tion in particle engineering areas such as nanoparticles, and applications requiring low-temperature processing. Few examples showing the utility of RESS in producing amorphous particles include ce-furoxime axetil (Varshosaz et al.2009), ibuprofen, and indomethacin (Pathak et al.

2004). Similarly, there are few examples demonstrating the potential of using SAS techniques to produce ASD, e.g., itraconazole (Lee et al.2005), rifampicin (Rever-chon et al.2002) and amoxicillin (Kalogiannis et al.2005). While some formulation and processing factors may be similar for SAS or RESS system, it is critical to op-timize the temperature and pressure in the SCF chamber to ensure that solubility conditions are fine-tuned to induce rapid supersaturation to ensure the precipitation of amorphous system.

The formulation and processing factors that can be tailored to customize the product attributes include:

• Use of cosolvents

• Nozzle dimension, spray rate, temperature, and pressure

• Conditions in the extraction chamber – Temperature

– Pressure – Volume

– Precipitation in aqueous phase with stabilizers (surfactants and polymers) The selection of SCF technology to produce ASD depends primarily on the solubility of API and polymer in the most commonly used SCF, supercritical CO2. Further formulation modification may be necessary to achieve desired particle morphology, e.g., polymers and surfactants are widely used to deagglomerate the particles and improve dissolution. Application of SCF in the development of ASD is still in its infancy, however, based on the flexibility in designing the process and properties of the SCF, it offers great potential for future advancement. For instance:

3 Overview of Amorphous Solid Dispersion Technologies 113

• Supercritical fluids could potentially enable the fastest rate of quenching and hence may open new possibilities in the solubilization space especially for challenging compounds.

• Differential solubility of API and polymer in the SCF may provide novel means of stabilizing the amorphous form.

• Processing temperatures may be suitable for thermo-labile compounds.

• By process design, the true particle size can be controlled in the submicron to nano range, thus offering dual advantage in improving the dissolution rate.

Once a suitable amorphous system has been produced, the downstream processing considerations will need to be addressed. Based on the nanoparticles work that has been conducted in this field, it is apparent that the amorphous product produced by the SCF will generally be of low density and high porosity and further densification will be required to make final dosage form.

3.6 KinetiSol

Poor aqueous solubility is a growing challenge in the pharmaceutical industry.

Although several technologies have been successfully developed to produce com-mercially viable products, there is still a need for newer technologies that can be applied to challenging compounds and/or provide additional benefit of simplifying the process or increasing drug load. KinetiSol^is a promising new technology that has specific advantage for compounds that cannot be processed with more estab-lished processes such as ASD and HME. Similar to microprecipitation technology, KinetiSol is developed to address the processing needs of difficult compounds that are limited by either high melting point and/or low solubility in volatile organic solvents (DiNunzio et al.2010; Hughey et al.2010).

The core aspect of the technology is a specific type of equipment that has been used in the plastic industry to mix high-melting, high-viscosity products. The primary mechanism of making amorphous form is a variation of the fusion method. Similar to HME, it utilizes the frictional and shear energy to melt the drug and polymer blend.

However, its distinguishing features are the intensity of mixing that causes material to melt within few seconds as opposed to HME where total residence time can vary from 30 s to few minutes. Faster heat transfer and melting result in shorter exposure time to high temperature that is specifically useful for high-melting and thermo-labile compounds. Due to the short exposure times, chemically labile compounds can be processed by KinetiSol^(Miller et al.2012). Although this technology is in the early stages of development, prototype equipment have already been designed to provide insights into scale-up and production. Laboratory-scale equipment is generally run in batch mode to conserve the API, however, the pilot- and production-scale equipment are being designed to run in semicontinuous mode with relatively high-throughput rate

In addition to being suitable for thermo-labile compounds, the short exposure to high temperature also expands the range of polymers that are generally not stable

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for high-temperature HME. From a downstream processing perspective, the material appears to be similar to HME and requires particle size reduction prior to processing into the final dosage form. Additives such as plasticizer and wetting agents may also be included to improve product performance.